In many areas of the world, insect bites are not just a nuisance; they are a serious danger to health. Most notably, such bites may result in the transmission of life threatening and debilitating diseases such as malaria, dengue fever, yellow fever, or the West Nile virus. Hence, there remains an ongoing need to improve the currently available insecticides.
Recent modeling work, based on population and malaria infection risk data in 20021, indicates that 61%—i.e. ca. 656 million cases—occur annually in the WHO Regions of the Americas, Southeast Asia and the Western Pacific. In 2005, the WHO reported that 41% of clinical malaria cases occur outside of Africa2, an increase in comparison to their 2001 estimate of 13.6%3. This growing awareness of the malaria problem beyond Africa should encourage the diversification of global research into malaria vector control—a matter of great importance, as mosquito vectors in these regions generally exhibit behavior that makes them less susceptible to control measures shown to be effective in sub-Saharan Africa, including insecticide treated bednets (ITNs) and indoor residual spraying (IRS).
These behaviors include tendencies of 1) outdoor resting, e.g. Anopheles darlingi4 and An. dirus5; 2) outdoor feeding, e.g. An. minimus,5 An. darlingi4, and An. sinensis5; and 3) significant feeding activity during early evening, e.g. An. albimanus,6 An. nunetzovari6, An. farauti No. 27, and An. darlingi.8 The introduction of ITNs in several areas also appears to have caused behavioral shifts among malaria vectors, with outdoor and early evening feeding becoming more frequent in areas where those control tools are in place9,10. A feasibility study for implementing ITNs in four Latin America countries showed that 25% of An. albimanus in Nicaragua, 28% of An. punctimacula in Ecuador, 57% of An. albimanus in Peru, and 30% of An. nunetzovari, also in Peru, fed before 9 p.m., when people are still active and often still outdoors.11 More recently, a case-control study in Colombia12 showed that ITNs provided only a 50% reduction in malaria, and this was attributed by the authors to mosquito's biting when people were not sleeping beneath the nets.
In such transmission conditions, ITNs may be usefully supplemented by insect repellents13,14. A recent household randomized trial in Pakistan15 has confirmed that the widespread provision of repellents—in this case, a repellent soap incorporating DEET and permethrin—can significantly reduce the risk of malaria by >50%. Furthermore, a clinical trial in the Bolivian Amazon,16 with a 30% p-menthane 3,8-diol (PMD) repellent showed an 80% reduction in P. vivax, among those using repellent and ITNs, compared to an ITN only group.
Much malaria and arbovirus transmission in the Americas is related to working practices, and the movement of non-immune people into malaria endemic areas in search of work in the forests (mining, logging etc).17 Young workers suffer the greatest hardship from this disease, which creates severe economic pressures for the whole family through loss of earnings,18 labor replacement, and treatment costs.19 For the poorest families in Latin America, these indirect costs may correspond to between 12 and 20% of annual household income19,20. With this in mind, a low cost repellent was developed that contains natural ingredients that are aromatically familiar to users and may eventually be sourced locally.
It is known that there are substances, including natural isolates, which can provide an insect repellency effect. Repellent substances are known to provide this effect when applied to a surface (e.g. human skin or hard surfaces) usually with an appropriate delivery vehicle (e.g. aerosol, lotion, spray, gel, etc.) and are commonly referred to as “insect or bug repellents”.
Examples of repellent materials which impart a repellency effect include, but are not limited to, materials such as N,N-diethyl m-toluamide (hereafter referred to as DEET), p-menthane-3,8-diol (commonly referred to as Coolact® 38D, registered trademark of Takasago International Corp.), permethrin, allethrin, piperonyl butoxide, lemongrass oil, citronella oil, eucalyptus oil, camphor, geranium oil, ethyl hexanediol, ethyl butylacetylaminopropionate, and hydroxyethyl-isobutyl-piperidine.
In a commercial repellent formulation, the repellent agents are typically added as a single active ingredient to produce the desired effect, it should be noted that there is at least two examples of a combination of two repellent materials being used in a composition. For example, U.S. Pat. No. 5,698,209 discloses a composition containing a monoterpenediol selected from carane-3,4-diol and p-menthane-3,8-diol (Coolact® 38D) and a pyrethroid compound selected from phenothrin and permethrin as active ingredients. The composition purportedly exhibits a high arthropod repellency for a long period of time. Also, Japanese Publication No. JP 3-133906 discloses a combination of p-menthane-3,8-diol and N,N-diethyl-m-toluamide (DEET). It should also be noted that there are other examples in the patent literature wherein an essential oil containing composition is claimed to possess repellent properties (see e.g., U.S. Published Application No. 2005/0112164 A1).
The active ingredient in a majority of commercial insect repellents is DEET which has been shown to be effective against a wide variety of biting insects. However, the use of DEET has several drawbacks including potential health risks and concerns, especially to children, since it is absorbed through human skin. In addition, the odor of DEET is considered by many to be “chemical” and unpleasant and it can sting when applied to the skin. Hence, a suitable consumer friendly repellent formulation is needed.